Compounds

ABSTRACT

The present invention provides compounds of formula 
                         
wherein R 1 , Y 1 , X 1 , Z 1 , X 2 , Y 2 , A, n and R 2  are as defined in the specification, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.

CROSS-REFERENCE TO RELATED APPLICATIONS RELATED APPLICATIONS

The present application claims the benefit of U.S. Provisional PatentApplication Ser. No. 60/869,930, filed Dec. 14, 2006, which is herebyincorporated by reference in its entirety.

NAMES OF PARTIES TO A JOINT RESEARCH AGREEMENT

The subject matter claimed in this application was made as a result ofactivities undertaken within the scope of a joint research agreementdated Dec. 19, 2003, between AstraZeneca AB and Sumitomo PharmaceuticalsCo., Ltd. All of the rights and obligations of Sumitomo PharmaceuticalsCo., Ltd. as defined in the joint research agreement between AstraZenecaAB and Sumitomo Pharmaceuticals Co., Ltd. were assumed by DainipponSumitomo Pharma Co., Ltd., a company created by the merger of DainipponPharmaceuticals Co., Ltd. and Sumitomo Pharmaceuticals Co., Ltd.effective Oct. 3, 2005.

BACKGROUND OF THE INVENTION

The present invention relates to adenine derivatives, processes fortheir preparation, pharmaceutical compositions containing them and theiruse in therapy.

The immune system is comprised of innate and acquired immunity, both ofwhich work cooperatively to protect the host from microbial infections.It has been shown that innate immunity can recognize conservedpathogen-associated molecular patterns through toll-like receptors(TLRs) expressed on the cell surface of immune cells. Recognition ofinvading pathogens then triggers cytokine production (includinginterferon alpha(IFNα)) and upregulation of co-stimulatory molecules onphagocytes, leading to modulation of T cell function. Thus, innateimmunity is closely linked to acquired immunity and can influence thedevelopment and regulation of an acquired response.

TLRs are a family of type I transmembrane receptors characterized by anNH₂-terminal extracellular leucine-rich repeat domain (LRR) and aCOOH-terminal intracellular tail containing a conserved region calledthe Toll/IL-1 receptor (TIR) homology domain. The extracellular domaincontains a varying number of LRR, which are thought to be involved inligand binding. Eleven TLRs have been described to date in humans andmice. They differ from each other in ligand specificities, expressionpatterns, and in the target genes they can induce.

Ligands which act via TLRs (also known as immune response modifiers(IRMS)) have been developed, for example, the imidazoquinolinederivatives described in U.S. Pat. No. 4,689,338 which include theproduct Imiquimod for treating genital warts, and the adeninederivatives described in WO 98/01448 and WO 99/28321.

This patent application describes a class of 9-substituted-8-oxoadeninecompounds having immuno-modulating properties which act via TLR7 thatare useful in the treatment of viral or allergic diseases and cancers.

In accordance with the present invention, there is therefore provided acompound of formula (I):

wherein

R¹ represents hydrogen, hydroxyl, C₁-C₆ alkoxy, C₂-C₅ alkoxycarbonyl,C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, or a C₆-C₁₀ aryl, C₅-C₁₀ heteroarylor C₃-C₈ cycloalkyl group, each group being optionally substituted byone or more substituents independently selected from halogen, hydroxyl,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₂-C₅alkoxycarbonyl, amino (NH₂) and di-C₁-C₆ alkylamino;

Y¹ represents a single bond or C₁-C₆ alkylene;

X¹ represents a single bond or an oxygen or sulphur atom or sulphonyl(SO₂) or NR³;

Z¹ represents a C₂-C₆ alkylene or C₃-C₈ cycloalkylene group, each ofwhich may be optionally substituted by at least one hydroxyl;

X² represents NR⁴, CONR⁴, NR⁴CO, SO₂NR⁴, NR⁴CONR⁵ or NR⁵CONR⁴, SO₂, CO,NR⁵CSNR⁵;

Y² represents a single bond or C₁-C₆ alkylene;

n is an integer 0, 1 or 2;

each R² group independently represents halogen, cyano, S(O)_(m)R⁹, OR¹⁰,SO₂NR¹⁰R¹¹, CONR¹⁰R¹¹, NR⁷R⁸, NR¹⁰SO₂R⁹, NR¹⁰CO₂R⁹, NR¹⁰COR⁹, C₆-C₁₀aryl, C₅-C₁₀ heteroaryl group, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynylor C₃-C₈ cycloalkyl group, the latter six groups being optionallysubstituted by one or more substituents independently selected fromhalogen, cyano, S(O)_(m)R¹², OR¹³, SO₂NR¹³R¹⁴, CONR¹³R¹⁴, NR⁷R⁸,NR¹³SO₂R¹², NR¹³CO₂R¹², NR¹³COR¹², C₁-C₆ alkyl or C₃-C₈cycloalkyl

R³ represents hydrogen or C₁-C₆ alkyl;

R⁴ represents hydrogen or a 3- to 8-membered saturated heterocyclic ringcomprising a ring group O or NR⁶;

or R⁴ represents a C₁-C₆ alkylene optionally substituted by one or moresubstituents independently selected from NR⁷R⁸ or R⁶;

R⁵ represents hydrogen or a C₁-C₆ alkyl or C₃-C₆ cycloalkyl group, eachof which may be optionally substituted by one or more substituentsindependently selected from halogen, hydroxyl and NR⁷R⁸;

R⁶ represents hydrogen, CO₂R⁹, SO₂R⁹, COR⁹, SO₂NR¹⁰R¹¹, CONR¹⁰R¹¹, a 3-to 8-membered saturated heterocyclic ring comprising a ring group NR⁹;or

(i) a C₆-C₁₀ aryl or C₅-C₁₀ heteroaryl group, each of which may beoptionally substituted by one or more substituents independentlyselected from halogen, cyano, oxo, carboxyl, S(O)_(m)R¹², OR¹³,SO₂NR¹³R¹⁴, CONR¹³R¹⁴, NR¹³R¹⁴, NR¹³SO₂R¹², NR¹³CO₂R¹², NR¹³COR¹², C₁-C₆alkyl and C₁-C₃ haloalkyl, or(ii) a C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl or C₃-C₈ cycloalkylgroup, each of which may be optionally substituted by one or moresubstituents independently selected from halogen, cyano, C₃-C₈cycloalkyl, OR¹⁵, S(O)_(p)R¹⁶, CO₂R¹⁶, NR¹⁷R¹⁸, CONR¹⁷R¹⁸, NR¹⁷COR¹⁶,SO₂NR¹⁷R¹⁸, NR¹⁷SO₂R¹⁶ and a group as defined in (i) above;

R⁷, R⁸, R¹³, R¹⁴R¹⁵, R¹⁹, R²², R²³, R²⁴ and R²⁵ each independentlyrepresent hydrogen, C₁-C₆ alkyl or C₃-C₆ cycloalkyl;

or R⁷ and R⁸ together with the nitrogen atom to which they are attachedform a 3- to 8-membered saturated heterocyclic ring comprising a ringnitrogen atom and optionally one or more further heteroatomsindependently selected from nitrogen, oxygen, sulphur and sulphonyl, theheterocyclic ring being optionally substituted by one or moresubstituents independently selected from halogen, hydroxyl, carboxyl,cyano, OR²¹, S(O)_(q)R²¹, NR²²R²³, C₁-C₆ alkyl and C₃-C₈ cycloalkyl;

R⁹, R¹⁶ and R²¹ each independently represent a C₁-C₆ alkyl or C₃-C₆cycloalkyl group, each of which may be optionally substituted by one ormore substituents independently selected from halogen, carboxyl,hydroxyl and NR¹⁹R²⁰;

either R¹⁰ represents hydrogen or a C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl or C₃-C₈ cycloalkyl group, each of which may be optionallysubstituted by one or more substituents independently selected fromhalogen, hydroxyl, carboxyl, cyano, OR²¹, S(O)_(q)R²¹, NR²²R²³ and C₃-C₈cycloalkyl, and

R¹¹ represents hydrogen or a C₁-C₆ alkyl or C₃-C₆ cycloalkyl group, eachof which may be optionally substituted by one or more substituentsindependently selected from halogen, hydroxyl and NR²⁴R²⁵, or

R¹⁰ and R¹¹ together with the nitrogen atom to which they are attachedform a 3- to 8-membered saturated heterocyclic ring comprising at leastone heteroatom or heterogroup selected from nitrogen, oxygen, sulphurand sulphonyl, the heterocyclic ring being optionally substituted by oneor more substituents independently selected from halogen, hydroxyl,carboxyl, cyano, OR²¹, S(O)_(q)R²¹, NR²²R²³, C₁-C₆ alkyl and C₃-C₈cycloalkyl;

R¹² represents C₁-C₆ alkyl or C₃-C₆ cycloalkyl;

R¹⁷ and R¹⁸ are defined as for R¹⁰ and R¹¹ respectively;

m, p and q each independently represent an integer 0, 1 or 2; and

A represents a monocyclic or bicyclic C₆-C₁₀ aryl or a monocyclic orbicyclic C₅-C₁₂ heteroaryl group containing 1-3 heteroatoms;

or a pharmaceutically acceptable salt thereof.

In the context of the present specification, unless otherwise stated, analkyl substituent group or an alkyl moiety in a substituent group may belinear or branched. Examples of C₁-C₆ alkyl groups/moieties includemethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl,n-pentyl and n-hexyl. Similarly, an alkylene group/moiety may be linearor branched. Examples of C₁-C₆ alkylene groups/moieties includemethylene, ethylene, n-propylene, n-butylene, n-pentylene, n-hexylene,1-methylethylene, 2-methylethylene, 1,2-dimethylethylene,1-ethylethylene, 2-ethylethylene, 1-, 2- or 3-methylpropylene and 1-, 2-or 3-ethylpropylene. A C₁-C₆ haloalkyl or C₁-C₆ haloalkoxy substituentgroup/moiety will comprise at least one halogen atom, e.g. one, two,three, four or five halogen atoms, examples of which includetrifluoromethyl, trifluoromethoxy or pentafluoroethyl. The alkyl groupsin a di-C₁-C₆ alkylamino or alkylcarbonyl group/moiety may be the sameas, or different from, one another. A C₁-C₆ hydroxyalkyl or C₁-C₆hydroxyalkoxy substituent group/moiety will comprise at least onehydroxyl group, e.g. one, two or three hydroxyl groups. An aryl orheteroaryl substituent group/moiety may be monocyclic or polycyclic(e.g. bicyclic or tricyclic) in which the two or more rings are fused. Aheteroaryl group/moiety will comprise at least one ring heteroatom (e.g.one, two, three or four ring heteroatoms independently) selected fromnitrogen, oxygen and sulphur. Examples of aryl and heteroarylgroups/moieties include phenyl, 1-naphthyl, 2-naphthyl, furyl, thienyl,pyrrolyl, pyridyl, indolyl, isoindolyl, quinolyl, isoquinolyl,pyrazolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyland oxazolyl.

A C₂-C₁₀ acyloxy group/moiety is exemplified by a C₂-C₅ alkylcarbonyloxygroup, a C₂-C₅ alkenylcarbonyloxy group, a C₂-C₅ alkynylcarbonyloxygroup, a C₆-C₉ arylcarbonyloxy group or a C₅-C₉ heteroarylcarbonyloxygroup, each of which may be optionally substituted by one or moresubstituents independently selected from halogen, hydroxyl, C₁-C₃ alkoxyor phenyl ring, optionally substituted by from halogen, hydroxyl, cyano,OR²¹, S(O)_(q)R²¹ or C₁-C₆ alkyl, providing that the total number ofcarbon atoms in the acyloxy group does not exceed 10.

Preferably R¹ represents hydrogen.

Preferably Y¹ represents C₁-C₆ alkylene, more preferably C₄ alkylene

Preferably X¹ represents oxygen

Preferably Z¹ represents C₂-C₆ alkylene, more preferably (CH₂)₃.

Preferably X² represents NR⁴.

Preferably Y² represents C₁-C₆ alkylene, more preferably a CH₂ group.

Preferably A represents phenyl

Preferably R² is hydrogen or C₁-C₆ alkoxy

Examples of compounds of the invention include:

-   6-Amino-9-{3-[benzyl(3-morpholin-4-ylpropyl)amino]propyl}-2-butoxy-7,9-dihydro-8H-purin-8-one-   6-Amino-2-butoxy-9-{3-[(4-isopropoxybenzyl)(3-morpholin-4-ylpropyl)amino]propyl}-7,9-dihydro-8H-purin-8-one-   6-Amino-2-butoxy-9-{3-[(4-methoxybenzyl)(3-morpholin-4-ylpropyl)amino]propyl}-7,9-dihydro-8H-purin-8-one-   6-Amino-2-butoxy-9-{3-[(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(3-morpholin-4-ylpropyl)amino]propyl}-7,9-dihydro-8H-purin-8-one-   6-Amino-2-butoxy-9-{3-[(3,4-dimethoxybenzyl)(3-morpholin-4-ylpropyl)amino]propyl}-7,9-dihydro-8H-purin-8-one-   6-Amino-2-butoxy-9-{3-[(4-morpholin-4-ylbenzyl)(3-morpholin-4-ylpropyl)amino]propyl}-7,9-dihydro-8H-purin-8-one-   6-Amino-2-butoxy-9-{3-[(3-morpholin-4-ylpropyl)(4-pyrimidin-2-ylbenzyl)amino]propyl}-7,9-dihydro-8H-purin-8-one-   6-Amino-2-butoxy-9-{3-[[4-(methylthio)benzyl](3-morpholin-4-ylpropyl)amino]propyl}-7,9-dihydro-8H-purin-8-one-   6-Amino-2-butoxy-9-(3-{(3-morpholin-4-ylpropyl)    [(2-oxo-2H-chromen-6-yl)methyl]amino}propyl)-7,9-dihydro-8H-purin-8-one-   6-Amino-2-butoxy-9-(3-{(3-morpholin-4-ylpropyl)    [(2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)methyl]amino}propyl)-7,9-dihydro-8H-purin-8-one-   6-Amino-2-butoxy-9-{3-[(3-morpholin-4-ylpropyl)(4-propoxybenzyl)amino]propyl}-7,9-dihydro-8H-purin-8-one-   6-Amino-2-butoxy-9-{3-[(3,5-dimethoxybenzyl)(3-morpholin-4-ylpropyl)amino]propyl}-7,9-dihydro-8H-purin-8-one-   6-Amino-2-butoxy-9-{3-[(2,4-dimethoxybenzyl)(3-morpholin-4-ylpropyl)amino]propyl}-7,9-dihydro-8H-purin-8-one-   (4-{[[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl](3-morpholin-4-ylpropyl)amino]methyl}phenoxy)acetonitrile-   6-Amino-2-butoxy-9-{3-[(3-morpholin-4-ylpropyl)(4-pyrrolidin-1-ylbenzyl)amino]propyl}-7,9-dihydro-8H-purin-8-one-   6-Amino-2-butoxy-9-(3-{(3-morpholin-4-ylpropyl)[4-(1H-1,2,4-triazol-1-yl)benzyl]amino}propyl)-7,9-dihydro-8H-purin-8-one-   6-Amino-2-butoxy-9-{3-[[4-(methylsulfonyl)benzyl](3-morpholin-4-ylpropyl)amino]propyl}-7,9-dihydro-8H-purin-8-one-   4-{[[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl](3-morpholin-4-ylpropyl)amino]methyl}-N-(tert-butyl)benzenesulfonamide-   6-Amino-2-butoxy-9-{3-[[4-(hydroxymethyl)benzyl](3-morpholin-4-ylpropyl)amino]propyl}-7,9-dihydro-8H-purin-8-one-   6-Amino-9-(3-{benzyl[2-(dimethylamino)ethyl]amino}propyl)-2-butoxy-7,9-dihydro-8H-purin-8-one-   6-Amino-9-{3-[benzyl(1-methylpiperidin-4-yl)amino]propyl}-2-butoxy-7,9-dihydro-8H-purin-8-one    and pharmaceutically acceptable salts or solvates thereof.

The present invention further provides a process for the preparation ofa compound of formula (I).

The present invention further provides a process for the preparation ofa compound of formula (I) or a pharmaceutically acceptable salt thereofas defined above which comprises,

(a) reacting a compound of formula

wherein Z¹, Y¹, X¹, R¹ and R⁴ are as defined in formula (I), with acompound of formula

wherein Y³ represents a bond or C₁-C₅ alkylene group and n and R² are asdefined in formula (I) in the presence of a suitable reducing agent(e.g. sodium triacetoxyborohydride); or(b) reacting a compound of formula (II) as defined in (a) above with acompound of formula

wherein Y⁴ represents C₁-C₅ alkylene group; L¹ represents a leavinggroup (e.g. halogen, mesylate or triflate) and n and R² are as definedin formula (I) in the presence of a suitable base (e.g. sodium carbonateor potassium carbonate), and optionally after carrying out one or moreof the following:converting the compound obtained to a further compound of the invention,removal of any protecting groups,forming a pharmaceutically acceptable salt of the compound; or

In process (a), the reaction may conveniently be carried out in anorganic solvent such as 1-methyl-2-pyrrolidinone, 1,2-dichloroethane ortetrahydrofuran at a temperature, for example, in the range from 0 to150° C.

In process (b), the reaction may conveniently be carried out in anorganic solvent such as acetonitrile, 1-methyl-2-pyrrolidinone orN,N-dimethylformamide at a temperature, for example, in the range from 0to 150° C.

Compounds of formula (II) where R¹ represents hydrogen, Y¹ representsC₁-C₆ alkylene, and X¹ represents oxygen may be prepared as illustratedin the following reaction scheme:

The compound of formula (B) is prepared by reacting the compound offormula (A) with ammonia in an organic solvent such as methanol,ethanol, propanol, butanol, tetrahydrofuran, 1,4-dioxane, diglyme,acetonitrile or an aqueous mixture of any one of the preceding solvents.The reaction may be carried out in an autoclave, and at a temperature,for example, in the range from 20 to 200° C.

Compounds of formula (C) may be prepared by reacting the compound offormula (B) with an alkanol in the presence of a base such as sodiumhydride and in an organic solvent such as tetrahydrofuran, 1,4-dioxane,diglyme, N,N-dimethylformamide or dimethylsulfoxide, preferably atelevated temperature, e.g. at a temperature in the range from 20 to 150°C. Alternatively an alkali metal such as sodium may be dissolved in thealkanol and then reacted with the compound of formula (B), preferably atelevated temperature, e.g. at a temperature in the range from 20 to 150°C.

Compounds of formula (D) are prepared by brominating a compound offormula (C). The reaction may be carried out using a brominating agentsuch as bromine, hydroperbromic acid or N-bromosuccinimide, in anorganic solvent such as carbon tetrachloride, methylene chloride,dichloroethane, diethyl ether, acetic acid or carbon disulfide. Thereaction temperature will generally be in the range from 0° C. to theboiling point of the solvent.

Compounds of formula (E) are prepared by reacting a compound of formula(D) with sodium methoxide in an organic solvent such as methanol and ata temperature, for example, in the range from 20 to 150° C.

Compounds of formula (F) may be obtained by treating a compound offormula (E) with an acid such as trifluoroacetic acid in an organicsolvent such as methanol.

Compounds of formula (G) are prepared by reacting a compound of formula(F) with a compound of formula LG-Z¹-LG wherein LG represents a leavinggroup such as a halogen, mesylate or triflate and Z¹ represents a C₂-C₆alkylene group as defined in formula (II). The reaction may be carriedout in an organic solvent such as N,N-dimethylformamide,dimethylsulfoxide or acetonitrile with a base present, preferably atroom temperature (20° C.). A base such as an alkali metal carbonate,e.g. sodium carbonate or potassium carbonate; an alkaline earth metalcarbonate, e.g. calcium carbonate; a metal hydroxide, e.g. sodiumhydroxide or potassium hydroxide; a metal hydrogenate, e.g. sodiumhydride; or a metal alkoxide, e.g. potassium t-butoxide, may be used.

Compounds of formula (H) may be obtained by treatment of a compound offormula (G) with an acid. The reaction may be carried out in an organicsolvent such as methanol using either an inorganic acid such ashydrochloric acid, hydrobromic acid or sulfuric acid, or an organic acidsuch as trifluoroacetic acid.

Compounds of formula (II) are prepared by reacting a compound of formula(H) with an amine of formula R⁴NH₂ where R⁴ is as defined in formula(I). The reaction may be carried out in an organic solvent such asacetonitrile or N,N-dimethylformamide using an excess of the amine,preferably at elevated temperature, e.g. at a temperature in the rangefrom 0 to 150° C.

It will be appreciated by those skilled in the art that in the processesof the present invention certain functional groups such as hydroxyl oramino groups in the reagents may need to be protected by protectinggroups. Thus, the preparation of the compounds of formula (I) mayinvolve, at an appropriate stage, the removal of one or more protectinggroups.

The protection and deprotection of functional groups is described in‘Protective Groups in Organic Chemistry’, edited by J. W. F. McOmie,Plenum Press (1973) and ‘Protective Groups in Organic Synthesis’, 3^(rd)edition, T. W. Greene and P. G. M. Wuts, Wiley-Interscience (1999).

The compounds of formula (I) above may be converted to apharmaceutically acceptable salt thereof, preferably an acid additionsalt such as a hydrochloride, hydrobromide, trifluoroacetate, sulphate,phosphate, acetate, fumarate, maleate, tartrate, lactate, citrate,pyruvate, succinate, oxalate, methanesulphonate or p-toluenesulphonate.

Compounds of formula (I) are capable of existing in stereoisomericforms. It will be understood that the invention encompasses the use ofall geometric and optical isomers (including atropisomers) of thecompounds of formula (I) and mixtures thereof including racemates. Theuse of tautomers and mixtures thereof also form an aspect of the presentinvention. Enantiomerically pure forms are particularly desired.

The compounds of formula (I) and their pharmaceutically acceptable saltshave activity as pharmaceuticals, in particular as modulators oftoll-like receptor (especially TLR7) activity, and thus may be used inthe treatment of:

1. respiratory tract: obstructive diseases of the airways including:asthma, including bronchial, allergic, intrinsic, extrinsic,exercise-induced, drug-induced (including aspirin and NSAID-induced) anddust-induced asthma, both intermittent and persistent and of allseverities, and other causes of airway hyper-responsiveness; chronicobstructive pulmonary disease (COPD); bronchitis, including infectiousand eosinophilic bronchitis; emphysema; bronchiectasis; cystic fibrosis;sarcoidosis; farmer's lung and related diseases; hypersensitivitypneumonitis; lung fibrosis, including cryptogenic fibrosing alveolitis,idiopathic interstitial pneumonias, fibrosis complicatinganti-neoplastic therapy and chronic infection, including tuberculosisand aspergillosis and other fungal infections; complications of lungtransplantation; vasculitic and thrombotic disorders of the lungvasculature, and pulmonary hypertension; antitussive activity includingtreatment of chronic cough associated with inflammatory and secretoryconditions of the airways, and iatrogenic cough; acute and chronicrhinitis including rhinitis medicamentosa, and vasomotor rhinitis;perennial and seasonal allergic rhinitis including rhinitis nervosa (hayfever); nasal polyposis; acute viral infection including the commoncold, and infection due to respiratory syncytial virus, influenza,coronavirus (including SARS) and adenovirus;2. skin: psoriasis, atopic dermatitis, contact dermatitis or othereczematous dermatoses, and delayed-type hypersensitivity reactions;phyto- and photodermatitis; seborrhoeic dermatitis, dermatitisherpetiformis, lichen planus, lichen sclerosus et atrophica, pyodermagangrenosum, skin sarcoid, discoid lupus erythematosus, pemphigus,pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitides,toxic erythemas, cutaneous eosinophilias, alopecia greata, male-patternbaldness, Sweet's syndrome, Weber-Christian syndrome, erythemamultiforme; cellulitis, both infective and non-infective; panniculitis;cutaneous lymphomas, non-melanoma skin cancer and other dysplasticlesions; drug-induced disorders including fixed drug eruptions;3. eyes: blepharitis; conjunctivitis, including perennial and vernalallergic conjunctivitis; iritis; anterior and posterior uveitis;choroiditis; autoimmune, degenerative or inflammatory disordersaffecting the retina; ophthalmitis including sympathetic ophthalmitis;sarcoidosis; infections including viral, fungal, and bacterial;4. genitourinary: nephritis including interstitial andglomerulonephritis; nephrotic syndrome; cystitis including acute andchronic (interstitial) cystitis and Hunner's ulcer; acute and chronicurethritis, prostatitis, epididymitis, oophoritis and salpingitis;vulvo-vaginitis; Peyronie's disease; erectile dysfunction (both male andfemale);5. allograft rejection: acute and chronic following, for example,transplantation of kidney, heart, liver, lung, bone marrow, skin orcornea or following blood transfusion; or chronic graft versus hostdisease;6. other auto-immune and allergic disorders including rheumatoidarthritis, irritable bowel syndrome, systemic lupus erythematosus,multiple sclerosis, Hashimoto's thyroiditis, Graves' disease, Addison'sdisease, diabetes mellitus, idiopathic thrombocytopaenic purpura,eosinophilic fasciitis, hyper-IgE syndrome, antiphospholipid syndromeand Sazary syndrome;7. oncology: treatment of common cancers including prostate, breast,lung, ovarian, pancreatic, bowel and colon, stomach, skin and braintumors and malignancies affecting the bone marrow (including theleukaemias) and lymphoproliferative systems, such as Hodgkin's andnon-Hodgkin's lymphoma; including the prevention and treatment ofmetastatic disease and tumour recurrences, and paraneoplastic syndromes;and,8. infectious diseases: virus diseases such as genital warts, commonwarts, plantar warts, hepatitis B, hepatitis C, herpes simplex virus,molluscum contagiosum, variola, human immunodeficiency virus (HIV),human papilloma virus (HPV), cytomegalovirus (CMV), varicella zostervirus (VZV), rhinovirus, adenovirus, coronavirus, influenza,para-influenza; bacterial diseases such as tuberculosis andmycobacterium avium, leprosy; other infectious diseases, such as fungaldiseases, chlamydia, candida, aspergillus, cryptococcal meningitis,pneumocystis carnii, cryptosporidiosis, histoplasmosis, toxoplasmosis,trypanosome infection and leishmaniasis.

Thus, the present invention provides a compound of formula (I) or apharmaceutically-acceptable salt thereof as hereinbefore defined for usein therapy.

In a further aspect, the present invention provides the use of acompound of formula (I) or a pharmaceutically acceptable salt thereof ashereinbefore defined in the manufacture of a medicament for use intherapy.

In the context of the present specification, the term “therapy” alsoincludes “prophylaxis” unless there are specific indications to thecontrary. The terms “therapeutic” and “therapeutically” should beconstrued accordingly.

Prophylaxis is expected to be particularly relevant to the treatment ofpersons who have suffered a previous episode of, or are otherwiseconsidered to be at increased risk of, the disease or condition inquestion. Persons at risk of developing a particular disease orcondition generally include those having a family history of the diseaseor condition, or those who have been identified by genetic testing orscreening to be particularly susceptible to developing the disease orcondition.

In particular, the compounds of the invention may be used in thetreatment of asthma, COPD, allergic rhinitis, allergic conjunctivitis,atopic dermatitis, cancer, hepatitis B, hepatitis C, HIV, HPV, bacterialinfections and dermatosis.

The anti-cancer treatment defined hereinbefore may be applied as a soletherapy or may involve, in addition to the compound of the invention,conventional surgery or radiotherapy or chemotherapy. Such chemotherapymay include one or more of the following categories of anti-tumouragents:—

(i) other antiproliferative/antineoplastic drugs and combinationsthereof, as used in medical oncology, such as alkylating agents (forexample cis-platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogenmustard, melphalan, chlorambucil, busulphan, temozolamide andnitrosoureas); antimetabolites (for example gemcitabine and antifolatessuch as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed,methotrexate, cytosine arabinoside, and hydroxyurea); antitumourantibiotics (for example anthracyclines like adriamycin, bleomycin,doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C,dactinomycin and mithramycin); antimitotic agents (for example vincaalkaloids like vincristine, vinblastine, vindesine and vinorelbine andtaxoids like taxol and taxotere and polokinase inhibitors); andtopoisomerase inhibitors (for example epipodophyllotoxins like etoposideand teniposide, amsacrine, topotecan and camptothecin);(ii) cytostatic agents such as antioestrogens (for example tamoxifen,fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene),antiandrogens (for example bicalutamide, flutamide, nilutamide andcyproterone acetate), LHRH antagonists or LHRH agonists (for examplegoserelin, leuprorelin and buserelin), progestogens (for examplemegestrol acetate), aromatase inhibitors (for example as anastrozole,letrozole, vorazole and exemestane) and inhibitors of5α-reductase such as finasteride;(iii) anti-invasion agents (for example c-Src kinase family inhibitorslike4-(6-chloro-2,3-methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4-yloxyquinazoline(AZD0530; International Patent Application WO 01/94341) andN-(2-chloro-6-methylphenyl)-2-{6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-ylamino}thiazole-5-carboxamide(dasatinib, BMS-354825; J. Med. Chem., 2004, 47, 6658-6661), andmetalloproteinase inhibitors like marimastat, inhibitors of urokinaseplasminogen activator receptor function or antibodies to Heparanase);(iv) inhibitors of growth factor function: for example such inhibitorsinclude growth factor antibodies and growth factor receptor antibodies(for example the anti-erbB2 antibody trastuzumab [Herceptin™], theanti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab[Erbitux®, C225] and any growth factor or growth factor receptorantibodies disclosed by Stern et al. Critical reviews inoncology/haematology, 2005, Vol. 54, pp 11-29); such inhibitors alsoinclude tyrosine kinase inhibitors, for example inhibitors of theepidermal growth factor family (for example EGFR family tyrosine kinaseinhibitors such asN-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine(gefitinib, ZD1839),N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine(erlotinib, OSI-774) and6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine(CI 1033), erbB2 tyrosine kinase inhibitors such as lapatinib,inhibitors of the hepatocyte growth factor family, inhibitors of theplatelet-derived growth factor family such as imatinib, inhibitors ofserine/threonine kinases (for example Ras/Raf signalling inhibitors suchas farnesyl transferase inhibitors, for example sorafenib (BAY43-9006)), inhibitors of cell signalling through MEK and/or AKT kinases,inhibitors of the hepatocyte growth factor family, c-kit inhibitors, ablkinase inhibitors, IGF receptor (insulin-like growth factor) kinaseinhibitors; aurora kinase inhibitors (for example AZD1152, PH739358,VX-680, MLN8054, R763, MP235, MP529, VX-528 AND AX39459) and cyclindependent kinase inhibitors such as CDK2 and/or CDK4 inhibitors;(v) antiangiogenic agents such as those which inhibit the effects ofvascular endothelial growth factor, [for example the anti-vascularendothelial cell growth factor antibody bevacizumab (Avastin™) and VEGFreceptor tyrosine kinase inhibitors such as4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline(ZD6474; Example 2 within WO 01/32651),4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline(AZD2171; Example 240 within WO 00/47212), vatalanib (PTK787; WO98/35985) and SU11248 (sunitinib; WO 01/60814), compounds such as thosedisclosed in International Patent Applications WO97/22596, WO 97/30035,WO 97/32856 and WO 98/13354 and compounds that work by other mechanisms(for example linomide, inhibitors of integrin α_(v)β3 function andangiostatin)];(vi) vascular damaging agents such as Combretastatin A4 and compoundsdisclosed in International Patent Applications WO 99/02166, WO 00/40529,WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;(vii) antisense therapies, for example those which are directed to thetargets listed above, such as ISIS 2503, an anti-ras antisense;(viii) gene therapy approaches, including for example approaches toreplace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2,GDEPT (gene-directed enzyme pro-drug therapy) approaches such as thoseusing cytosine deaminase, thymidine kinase or a bacterial nitroreductaseenzyme and approaches to increase patient tolerance to chemotherapy orradiotherapy such as multi-drug resistance gene therapy; and(ix) immunotherapy approaches, including for example ex-vivo and in-vivoapproaches to increase the immunogenicity of patient tumour cells, suchas transfection with cytokines such as interleukin 2, interleukin 4 orgranulocyte-macrophage colony stimulating factor, approaches to decreaseT-cell anergy, approaches using transfected immune cells such ascytokine-transfected dendritic cells, approaches usingcytokine-transfected tumour cell lines and approaches usinganti-idiotypic antibodies.

The invention still further provides a method of treating, or reducingthe risk of, an obstructive airways disease or condition (e.g. asthma orCOPD) which comprises administering to a patient in need thereof atherapeutically effective amount of a compound of formula (I) or apharmaceutically acceptable salt thereof as hereinbefore defined.

For the above-mentioned therapeutic uses the dosage administered will,of course, vary with the compound employed, the mode of administration,the treatment desired and the disorder indicated. For example, the dailydosage of the compound of the invention, if inhaled, may be in the rangefrom 0.05 micrograms per kilogram body weight (μg/kg) to 100 microgramsper kilogram body weight (μg/kg). Alternatively, if the compound isadministered orally, then the daily dosage of the compound of theinvention may be in the range from 0.01 micrograms per kilogram bodyweight (μg/kg) to 100 milligrams per kilogram body weight (mg/kg).

The compounds of formula (I) and pharmaceutically acceptable saltsthereof may be used on their own but will generally be administered inthe form of a pharmaceutical composition in which the formula (I)compound/salt (active ingredient) is in association with apharmaceutically acceptable adjuvant, diluent or carrier. Conventionalprocedures for the selection and preparation of suitable pharmaceuticalformulations are described in, for example, “Pharmaceuticals—The Scienceof Dosage Form Designs”, M. E. Aulton, Churchill Livingstone, 1988.

Depending on the mode of administration, the pharmaceutical compositionwill preferably comprise from 0.05 to 99% w (percent by weight), morepreferably from 0.05 to 80% w, still more preferably from 0.10 to 70% w,and even more preferably from 0.10 to 50% w, of active ingredient, allpercentages by weight being based on total composition.

The present invention also provides a pharmaceutical compositioncomprising a compound of formula (I) or a pharmaceutically acceptablesalt thereof as hereinbefore defined, in association with apharmaceutically acceptable adjuvant, diluent or carrier.

The invention further provides a process for the preparation of apharmaceutical composition of the invention which comprises mixing acompound of formula (I) or a pharmaceutically acceptable salt thereof ashereinbefore defined with a pharmaceutically acceptable adjuvant,diluent or carrier.

The pharmaceutical compositions may be administered topically (e.g. tothe skin or to the lung and/or airways) in the form, e.g., of creams,solutions, suspensions, heptafluoroalkane (HFA) aerosols and dry powderformulations, for example, formulations in the inhaler device known asthe Turbuhaler®; or systemically, e.g. by oral administration in theform of tablets, capsules, syrups, powders or granules; or by parenteraladministration in the form of solutions or suspensions; or bysubcutaneous administration; or by rectal administration in the form ofsuppositories; or transdermally.

Dry powder formulations and pressurized HFA aerosols of the compounds ofthe invention (including pharmaceutically acceptable salts) may beadministered by oral or nasal inhalation. For inhalation, the compoundis desirably finely divided. The finely divided compound preferably hasa mass median diameter of less than 10 micrometres (μm), and may besuspended in a propellant mixture with the assistance of a dispersant,such as a C₈-C₂₀ fatty acid or salt thereof, (for example, oleic acid),a bile salt, a phospholipid, an alkyl saccharide, a perfluorinated orpolyethoxylated surfactant, or other pharmaceutically acceptabledispersant.

The compounds of the invention may also be administered by means of adry powder inhaler. The inhaler may be a single or a multi dose inhaler,and may be a breath actuated dry powder inhaler.

One possibility is to mix the finely divided compound of the inventionwith a carrier substance, for example, a mono-, di- or polysaccharide, asugar alcohol, or another polyol. Suitable carriers are sugars, forexample, lactose, glucose, raffinose, melezitose, lactitol, maltitol,trehalose, sucrose, mannitol; and starch. Alternatively the finelydivided compound may be coated by another substance. The powder mixturemay also be dispensed into hard gelatine capsules, each containing thedesired dose of the active compound.

Another possibility is to process the finely divided powder into sphereswhich break up during the inhalation procedure. This spheronized powdermay be filled into the drug reservoir of a multidose inhaler, forexample, that known as the Turbuhaler® in which a dosing unit meters thedesired dose which is then inhaled by the patient. With this system theactive ingredient, with or without a carrier substance, is delivered tothe patient.

For oral administration the compound of the invention may be admixedwith an adjuvant or a carrier, for example, lactose, saccharose,sorbitol, mannitol; a starch, for example, potato starch, corn starch oramylopectin; a cellulose derivative; a binder, for example, gelatine orpolyvinylpyrrolidone; and/or a lubricant, for example, magnesiumstearate, calcium stearate, polyethylene glycol, a wax, paraffin, andthe like, and then compressed into tablets. If coated tablets arerequired, the cores, prepared as described above, may be coated with aconcentrated sugar solution which may contain, for example, gum arabic,gelatine, talcum and titanium dioxide. Alternatively, the tablet may becoated with a suitable polymer dissolved in a readily volatile organicsolvent.

For the preparation of soft gelatine capsules, the compound of theinvention may be admixed with, for example, a vegetable oil orpolyethylene glycol. Hard gelatine capsules may contain granules of thecompound using either the above-mentioned excipients for tablets. Alsoliquid or semisolid formulations of the compound of the invention may befilled into hard gelatine capsules.

Liquid preparations for oral application may be in the form of syrups orsuspensions, for example, solutions containing the compound of theinvention, the balance being sugar and a mixture of ethanol, water,glycerol and propylene glycol. Optionally such liquid preparations maycontain colouring agents, flavouring agents, saccharine and/orcarboxymethylcellulose as a thickening agent or other excipients knownto those skilled in art.

The compounds of the invention may also be administered in conjunctionwith other compounds used for the treatment of the above conditions.

The invention therefore further relates to combination therapies whereina compound of the invention or a pharmaceutical composition orformulation comprising a compound of the invention is administeredconcurrently or sequentially or as a combined preparation with anothertherapeutic agent or agents, for the treatment of one or more of theconditions listed.

In particular, for the treatment of the inflammatory diseases COPD,asthma and allergic rhinitis the compounds of the invention may becombined with agents such as tumour necrosis factor alpha (TNF-alpha)inhibitors such as anti-TNF monoclonal antibodies (for exampleinfliximab [Remicade®], CDP-870 and adalimumab) and TNF receptorimmunoglobulin molecules (such as entanercept [Enbrel®]); non-selectivecyclo-oxygenase COX-1/COX-2 inhibitors whether applied topically orsystemically (such as piroxicam, diclofenac, propionic acids such asnaproxen, flubiprofen, fenoprofen, ketoprofen and ibuprofen, fenamatessuch as mefenamic acid, indomethacin, sulindac, azapropazone,pyrazolones such as phenylbutazone, salicylates such as aspirin), COX-2inhibitors (such as meloxicam, celecoxib, rofecoxib, valdecoxib,lumarocoxib, parecoxib and etoricoxib); glucocorticosteroids (whetheradministered by topical, oral, intramuscular, intravenous, orintra-articular routes); methotrexate, lefunomide; hydroxychloroquine,d-penicillamine, auranofin or other parenteral or oral goldpreparations.

The present invention still further relates to the combination of acompound of the invention and a leukotriene biosynthesis inhibitor,5-lipoxygenase (5-LO) inhibitor or 5-lipoxygenase activating protein(FLAP) antagonist such as; zileuton; ABT-761; fenleuton; tepoxalin;Abbott®-79175; Abbott®-85761; aN-(5-substituted)-thiophene-2-alkylsulfonamide;2,6-di-tert-butylphenolhydrazones; a methoxytetrahydropyrans such asZeneca® ZD-2138; the compound SB-210661; a pyridinyl-substituted2-cyanonaphthalene compound such as L-739,010; a 2-cyanoquinolinecompound such as L-746,530; or an indole or quinoline compound such asMK-591, MK-886, and BAY x 1005.

The present invention further relates to the combination of a compoundof the invention and a receptor antagonist for leukotrienes (LT B4,LTC4, LTD4, and LTE4) selected from the group consisting of thephenothiazin-3-1s such as L-651,392; amidino compounds such asCGS-25019c; benzoxalamines such as ontazolast; benzenecarboximidamidessuch as BIIL 284/260; and compounds such as zafirlukast, ablukast,montelukast, pranlukast, verlukast (MK-679), RG-12525, Ro-245913,iralukast (CGP 45715A), and BAY x 7195.

The present invention still further relates to the combination of acompound of the invention and a phosphodiesterase (PDE) inhibitor suchas a methylxanthanine including theophylline and aminophylline; aselective PDE isoenzyme inhibitor including a PDE4 inhibitor aninhibitor of the isoform PDE4D, or an inhibitor of PDE5.

The present invention further relates to the combination of a compoundof the invention and a histamine type 1 receptor antagonist such ascetirizine, loratadine, desloratadine, fexofenadine, acrivastine,terfenadine, astemizole, azelastine, levocabastine, chlorpheniramine,promethazine, cyclizine, or mizolastine; applied orally, topically orparenterally.

The present invention still further relates to the combination of acompound of the invention and a gastroprotective histamine type 2receptor antagonist.

The present invention further relates to the combination of a compoundof the invention and an antagonist of the histamine type 4 receptor.

The present invention still further relates to the combination of acompound of the invention and an alpha-1/alpha-2 adrenoceptor agonistvasoconstrictor sympathomimetic agent, such as propylhexedrine,phenylephrine, phenylpropanolamine, ephedrine, pseudoephedrine,naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozolinehydrochloride, xylometazoline hydrochloride, tramazoline hydrochlorideor ethylnorepinephrine hydrochloride.

The present invention further relates to the combination of a compoundof the invention and an anticholinergic agent including muscarinicreceptor (M1, M2, and M3) antagonists such as atropine, hyoscine,glycopyrrrolate, ipratropium bromide, tiotropium bromide, oxitropiumbromide, pirenzepine or telenzepine.

The present invention still further relates to the combination of acompound of the invention together with a beta-adrenoceptor agonist(including beta receptor subtypes 1-4) such as isoprenaline, salbutamol,formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate,and pirbuterol.

The present invention further relates to the combination of a compoundof the invention and a chromone, such as sodium cromoglycate ornedocromil sodium.

The present invention still further relates to the combination of acompound of the invention together with an insulin-like growth factortype I (IGF-1) mimetic.

The present invention still further relates to the combination of acompound of the invention and a glucocorticoid, such as flunisolide,triamcinolone acetonide, beclomethasone dipropionate, budesonide,fluticasone propionate, ciclesonide or mometasone furoate.

The present invention still further relates to the combination of acompound of the invention together with an inhibitor of matrixmetalloproteases (MMPs), i.e., the stromelysins, the collagenases, andthe gelatinases, as well as aggrecanase; especially collagenase-1(MMP-1), collagenase-2 (MMP-8), collagenase-3 (MMP-13), stromelysin-1(MMP-3), stromelysin-2 (MMP-10), and stromelysin-3 (MMP-11) and MMP-9and MMP-12.

The present invention still further relates to the combination of acompound of the invention together with modulators of chemokine receptorfunction such as antagonists of CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4,CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11 (for the C—C family);CXCR1, CXCR2, CXCR3, CXCR4 and CXCR5 (for the C—X—C family) and CX3CR1for the C—X3-C family.

The present invention still further relates to the combination of acompound of the invention together with a cytokine or modulator ofcytokine function, including alpha-, beta-, and gamma-interferon;interleukins (IL) including IL1 to 15, and interleukin antagonists orinhibitors, including agents which act on cytokine signalling pathways.

The present invention still further relates to the combination of acompound of the invention together with an immunoglobulin (Ig) or Igpreparation or an antagonist or antibody modulating Ig function such asanti-IgE (omalizumab).

The present invention further relates to the combination of a compoundof the invention and another systemic or topically-appliedanti-inflammatory agent, such as thalidomide or a derivative thereof, aretinoid, dithranol or calcipotriol.

The present invention further relates to the combination of a compoundof the invention together with an antibacterial agent such as apenicillin derivative, a tetracycline, a macrolide, a beta-lactam, afluoroquinolone, metronidazole, an inhaled aminoglycoside; an antiviralagent including acyclovir, famciclovir, valaciclovir, ganciclovir,cidofovir, amantadine, rimantadine, ribavirin, zanamavir andoseltamavir; a protease inhibitor such as indinavir, nelfinavir,ritonavir, and saquinavir; a nucleoside reverse transcriptase inhibitorsuch as didanosine, lamivudine, stavudine, zalcitabine or zidovudine; ora non-nucleoside reverse transcriptase inhibitor such as nevirapine orefavirenz.

A compound of the invention can also be used in combination with anexisting therapeutic agent for the treatment of cancer, for examplesuitable agents include:

(i) an antiproliferative/antineoplastic drug or a combination thereof,as used in medical oncology, such as an alkylating agent (for examplecis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan,chlorambucil, busulphan or a nitrosourea); an antimetabolite (forexample an antifolate such as a fluoropyrimidine like 5-fluorouracil ortegafur, raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea,gemcitabine or paclitaxel); an antitumour antibiotic (for example ananthracycline such as adriamycin, bleomycin, doxorubicin, daunomycin,epirubicin, idarubicin, mitomycin-C, dactinomycin or mithramycin); anantimitotic agent (for example a vinca alkaloid such as vincristine,vinblastine, vindesine or vinorelbine, or a taxoid such as taxol ortaxotere); or a topoisomerase inhibitor (for example anepipodophyllotoxin such as etoposide, teniposide, amsacrine, topotecanor a camptothecin);(ii) a cytostatic agent such as an antioestrogen (for example tamoxifen,toremifene, raloxifene, droloxifene or iodoxyfene), an oestrogenreceptor down regulator (for example fulvestrant), an antiandrogen (forexample bicalutamide, flutamide, nilutamide or cyproterone acetate), aLHRH antagonist or LHRH agonist (for example goserelin, leuprorelin orbuserelin), a progestogen (for example megestrol acetate), an aromataseinhibitor (for example as anastrozole, letrozole, vorazole orexemestane) or an inhibitor of 5α-reductase such as finasteride;(iii) an agent which inhibits cancer cell invasion (for example ametalloproteinase inhibitor like marimastat or an inhibitor of urokinaseplasminogen activator receptor function);(iv) an inhibitor of growth factor function, for example: a growthfactor antibody (for example the anti-erbb2 antibody trastuzumab, or theanti-erbb1 antibody cetuximab [C225]), a farnesyl transferase inhibitor,a tyrosine kinase inhibitor or a serine/threonine kinase inhibitor, aninhibitor of the epidermal growth factor family (for example an EGFRfamily tyrosine kinase inhibitor such asN-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine(gefitinib, AZD1839),N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine(erlotinib, OSI-774) or6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine(CI 1033)), an inhibitor of the platelet-derived growth factor family,or an inhibitor of the hepatocyte growth factor family;(v) an antiangiogenic agent such as one which inhibits the effects ofvascular endothelial growth factor (for example the anti-vascularendothelial cell growth factor antibody bevacizumab, a compounddisclosed in WO 97/22596, WO 97/30035, WO 97/32856 or WO 98/13354), or acompound that works by another mechanism (for example linomide, aninhibitor of integrin α_(v)β₃ function or an angiostatin);(vi) a vascular damaging agent such as combretastatin A4, or a compounddisclosed in WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO02/04434 or WO 02/08213;(vii) an agent used in antisense therapy, for example one directed toone of the targets listed above, such as ISIS 2503, an anti-rasantisense;(viii) an agent used in a gene therapy approach, for example approachesto replace aberrant genes such as aberrant p53 or aberrant BRCA1 orBRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such asthose using cytosine deaminase, thymidine kinase or a bacterialnitroreductase enzyme and approaches to increase patient tolerance tochemotherapy or radiotherapy such as multi-drug resistance gene therapy;or(ix) an agent used in an immunotherapeutic approach, for example ex-vivoand in-vivo approaches to increase the immunogenicity of patient tumourcells, such as transfection with cytokines such as interleukin 2,interleukin 4 or granulocyte-macrophage colony stimulating factor,approaches to decrease T-cell anergy, approaches using transfectedimmune cells such as cytokine-transfected dendritic cells, approachesusing cytokine-transfected tumour cell lines and approaches usinganti-idiotypic antibodies.

The present invention will be further explained by reference to thefollowing illustrative examples.

The following abbreviations are used;

EtOAc ethyl acetate DCM dichloromethane NMP N-methylpyrrolidine NBSN-bromosuccinamide DMF N, N-dimethylformamide DMSO dimethylsulfoxide THFtetrahydrofuran TFA trifluoroacetic acid mcpba 3-chloroperoxybenzoicacid (Aldrich 77% max) rt room temperature h hours min minutes M molarMS mass spectrometry APCI atmospheric pressure chemical ionisation NMRnuclear magnetic resonance HCl hydrochloric acid BOCtertiary-butoxycarbonyl HOBt 1-hydroxybenzotriazole EDC1-(3-dimethylamino propyl)-3-ethylcarbodiimide hydrochloride HATUO-(7-azabenzotriazol-1-yl)-N, N, N′, N′-tetramethyluroniumhexafluorophosphonate

Unless otherwise stated organic solutions were dried over magnesiumsulphate. RPHPLC denotes Reverse Phase Preparative High PerformanceLiquid Chromatography using Waters® Symmetry® C8, XTerra® or Phenomenex®Gemini™ columns using acetonitrile and either aqueous ammonium acetate,ammonia, formic acid or trifluoroacetic acid as buffer whereappropriate. Column chromatography was carried out on silica gel. SCXdenotes solid phase extraction with a sulfonic acid sorbent whereby amixture was absorbed on a sulfonic acid sorbent and eluted with anappropriate solvent such as methanol or acetonitrile and then the freebase product was eluted with aqueous ammonia/an appropriate solvent suchas methanol or acetonitrile.

Biological Assay

Human TLR7 Assay

Recombinant human TLR7 was stably expressed in a HEK293 cell linealready stably expressing the pNiFty2-SEAP reporter plasmid; integrationof the reporter gene was maintained by selection with the antibioticzeocin. The most common variant sequence of human TLR7 (represented bythe EMBL sequence AF240467) was cloned into the mammalian cellexpression vector pUNO and transfected into this reporter cell-line.Transfectants with stable expression were selected using the antibioticblasticidin. In this reporter cell-line, expression of secreted alkalinephosphatase (SEAP) is controlled by an NFkB/ELAM-1 composite promotercomprising five NFkB sites combined with the proximal ELAM-1 promoter.TLR signaling leads to the translocation of NFkB and activation of thepromoter results in expression of the SEAP gene. TLR7-specificactivation was assessed by determining the level of SEAP producedfollowing overnight incubation of the cells at 37° C. with the standardcompound in the presence of 0.1% (v/v) dimethylsulfoxide (DMSO).Concentration dependent induction of SEAP production by compounds wasexpressed as the log of the minimal effective concentration of compoundto induce SEAP release (pMEC).

Compound of Example: 8 pMEC 7.2 12 >7.7 16 7.4

EXPERIMENTAL

Unless otherwise stated organic solutions were dried over magnesiumsulphate. RPHPLC means reversed phase preparative HPLC using Waters®Symmetry® C8, XTerra® or Phenomenex® Gemini™ columns using acetonitrileand either aqueous ammonium acetate, ammonia, formic acid ortrifluoroacetic acid as buffer where appropriate. Column chromatographywas carried out on silica gel. Treating with SCX means the mixture wasabsorbed on SCX and eluted with an appropriate solvent such as methanolor acetonitrile then the free base product eluted with aqueousammonia/methanol.

Example 16-Amino-9-{3-[benzyl(3-morpholin-4-ylpropyl)amino]propyl}-2-butoxy-7,9-dihydro-8H-purin-8-one

(i) 2-Chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine

2,6-Dichloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (55 g) was dissolvedin 7N-aqueous ammonia in methanol (500 ml) and heated at 100° C. in asealed flask for 6 hours. The reaction mixture was cooled to roomtemperature and left overnight. Filtration afforded the subtitlecompound. Yield 40 g.

¹H NMR δ (CDCl₃) 8.02 (1H, s), 5.94 (2H, brs), 5.71 (1H, dd), 4.15-4.22(1H, m), 3.75-3.82 (1H, m), 1.27-2.12 (6H, m).

(ii) 2-Butoxy-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine

The product from step (i) (40 g) was dissolved in 19% (w/w)-sodiumbutoxide in butanol (250 ml). The reaction mixture was stirred underreflux for 6 hours. The resultant suspension was cooled to roomtemperature, diluted with water and extracted with diethyl ether. Thecombined organic phase was washed with water, dried and concentrated invacuo. The subtitle compound was crystallised from diethylether/isohexane (1/1, 300 ml) and obtained by filtration. Yield 19 g.

¹H NMR δ (CDCl₃) 7.87 (1H, s), 5.56-5.68 (3H, m), 4.31-4.35 (2H, t),4.14-4.17 (1H, m), 3.76-3.80 (1H, m), 1.49-2.08 (10H, m), 0.98 (3H, t).

(iii) 8-Bromo-2-butoxy-9-(tetrahydro-2H-pyran-2-yl) 9H-purin-6-amine

The product from step (ii) (30 g) was dissolved in dry dichloromethane(200 ml). The solution was stirred at room temperature whilstN-bromosuccinamide (27 g) was added portionwise. The mixture was stirredat ambient temperature overnight. 20% (w/v)-Sodium sulfate (200 ml) wasadded and the separated aqueous phase extracted with dichloromethane.The combined organic phase was washed with saturated sodium hydrogencarbonate solution and brine. After concentration in vacuo, the residuewas dissolved in ethyl acetate, washed with water, brine and dried. Thesolution was filtered through silica gel and concentrated in vacuo. Theresidue was triturated with diethyl ether and isohexane (1/1, 200 ml)then filtered to give the subtitle compound (26 g). The filtrate wasconcentrated in vacuo and the residue purified by column chromatography(ethyl acetate/isohexane) to give a further 2.5 g of product. The solidswere combined to give the subtitle compound as a yellow solid. Yield28.5 g. mp 148-50° C.

¹H NMR δ (CDCl₃) 5.59-5.64 (3H, m), 4.32 (2H, m), 4.17 (1H, m), 3.74(1H, m), 3.08 (1H, m), 2.13 (1H, d), 1.48-1.83 (8H, m), 0.98 (3H, t).

(iv) 2-Butoxy-8-methoxy-9-(tetrahydro-2H-pyran-2-yl)9H-purin-6-amine

Sodium (3.7 g) was added to absolute methanol (400 ml) under a nitrogenatmosphere. To this solution was added the product from step (iii) (28.5g) and the mixture was stirred at 65° C. for 9 hours. The mixture wasconcentrated in vacuo and 500 ml of water added. The aqueous phase wasextracted with ethyl acetate, washed with brine and dried. The subtitlecompound was obtained after crystallisation from diethyl ether. Yield14.2 g.

¹H NMR δ (CDCl₃) 5.51 (1H, dd), 5.28 (2H, brs), 4.29 (2H, t), 4.11-4.14(4H, m), 3.70 (1H, m), 2.76-2.80 (1H, m), 2.05 (1H, d), 1.47-1.81 (8H,m), 0.97 (3H, t).

(v) 2-Butoxy-8-methoxy-9H-purin-6-amine, TFA salt

The product from step (iv) (24 g) was dissolved in absolute methanol(300 ml) and 30 ml of trifluoroacetic acid was added. The reactionmixture was stirred at ambient temperature for 3 days and concentratedin vacuo. The subtitle compound was obtained as a white crystallinesolid after trituration with methanol/ethyl acetate. Yield 21 g.

¹H NMR δ (CD₃OD) 4.48 (2H, t), 4.15 (3H, s), 1.80 (2H, quintet), 1.50(2H, sextet), 0.99 (3H, t).

(vi) 9-(3-Bromopropyl)-2-butoxy-8-methoxy-9H-purin-6-amine

The product of step (v) (20 g) was added in portions over 10 minutes toa rapidly stirred mixture of potassium carbonate (40 g) and1,3-dibromopropane (34 ml) in N,N-dimethylformamide (250 ml) at ambienttemperature and the mixture stirred for 1.5 hours. The mixture wasdiluted with water and extracted with ethyl acetate. The combinedextracts were washed with brine and dried. The mixture was purified bycolumn chromatography (ethyl acetate), to afford the subtitle compoundas a white solid. Yield 16 g.

¹H NMR δ (CDCl₃) 5.19 (2H, s), 4.28 (2H, J=6.7 Hz, t), 4.12 (3H, s),4.09 (2H, J=9.4 Hz, t), 3.37 (2H, J=13.3 Hz, t), 2.39-2.30 (2H, m),1.81-1.72 (2H, m), 1.55-1.43 (2H, m), 0.96 (3H, J=11.4 Hz, t).

(vii) 6-Amino-9-(3-bromopropyl)-2-butoxy-7,9-dihydro-8H-purin-8-one

The product of step (vi) (35.8 g) was dissolved in methanol (400 ml) andtreated with 4M hydrogen chloride in dioxane (100 ml). The mixture wasstirred at ambient temperature for 6 hours and concentrated in vacuo.Dichloromethane (500 ml) was added and concentrated in vacuo, whichafforded a foam that was taken onto the next step without furtherpurification. Yield 38 g.

¹H NMR δ (DMSO-d₆) 10.60 (1H, s), 4.45 (2H, m), 3.84 (2H, m), 3.65 (2H,m), 2.19 (2H, m), 1.66-1.73 (2H, m), 1.36-1.47 (2H, m), 0.96 (3H, m).

(viii)6-Amino-2-butoxy-9-{3-[(3-morpholin-4-ylpropyl)amino]propyl}-7,9-dihydro-8H-purin-8-one

The product of step (vii) (4 g) was suspended in acetonitrile (40 ml)and 4-(3-aminopropyl)morpholine (15 ml) was added. The mixture wasstirred under reflux for 14 h. then the mixture evaporated under reducedpressure. The residue was purified by RPHPLC. Yield 3.59 g.

MS: APCI (+ve): 408 (M+H)

(ix)6-Amino-9-{3-[benzyl(3-morpholin-4-ylpropyl)amino]propyl}-2-butoxy-7,9-dihydro-8H-purin-8-one

6-Amino-2-butoxy-9-[3-(3-morpholin-4-yl-propylamino)-propyl]-7,9-dihydro-purin-8-one(0.1 g), Benzaldehyde (0.03125 g, 0.03005 ml) were combined in NMP (1.5mL) and stirred at RT for 15 mins. Sodium triacetoxyborohydride (0.078g) was added and the reaction mixture was stirred for 16 h. The reactionmixture was diluted with methanol and purified by RPHPLC to give thetitle compound (0.068 g)

¹H NMR δ (DMSO-d₆) 0.90 (3H, t), 1.31-1.42 (2H, m), 1.44-1.54 (2H, m),1.56-1.67 (2H, m), 1.77-1.88 (2H, m), 2.14-2.30 (6H, m), 2.32-2.44 (4H,m), 3.43-3.52 (6H, m), 3.64-3.72 (2H, m), 4.06-4.17 (2H, m), 6.37 (2H,s), 7.17-7.29 (5H, m), 9.80 (1H, s)

MS: APCI (+ve): 498 (M+H)

Examples 2-16 were prepared by the method of example 1

Example 26-Amino-2-butoxy-9-{3-[(4-isopropoxybenzyl)(3-morpholin-4-ylpropyl)amino]propyl}-7,9-dihydro-8H-purin-8-one

¹H NMR δ (DMSO-d₆) 0.82-0.95 (3H, m), 1.30-1.40 (4H, m), 1.43-1.53 (2H,m), 1.57-1.67 (2H, m), 1.76-1.86 (2H, m), 2.15-2.24 (3H, m), 2.30-2.39(3H, m), 2.67 (1H, s), 2.99-3.09 (4H, m), 3.39 (2H, s), 3.44-3.54 (4H,m), 3.61-3.77 (6H, m), 4.12 (2H, t), 6.38 (2H, s), 6.82 (2H, d), 7.10(2H, d)

MS: APCI (+ve): 556 (M+H)

Example 36-Amino-2-butoxy-9-{3-[(4-methoxybenzyl)(3-morpholin-4-ylpropyl)amino]propyl}-7,9-dihydro-8H-purin-8-one

¹H NMR δ (DMSO-d₆) 0.90 (3H, t), 1.32-1.42 (2H, m), 1.44-1.53 (2H, m),1.57-1.66 (2H, m), 1.77-1.86 (2H, m), 2.14-2.26 (6H, m), 2.29-2.42 (4H,m), 3.42 (2H, s), 3.45-3.52 (4H, m), 3.63-3.71 (2H, m), 3.72 (3H, s),4.08-4.16 (2H, m), 6.38 (2H, s), 6.82 (2H, d), 7.16 (2H, d), 9.82 (1H,s)

MS: APCI (+ve): 528 (M+H)

Example 46-Amino-2-butoxy-9-{3-[(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(3-morpholin-4-ylpropyl)amino]propyl}-7,9-dihydro-8H-purin-8-one

¹H NMR δ (DMSO-d₆) 0.90 (3H, t), 1.31-1.41 (2H, m), 1.43-1.52 (2H, m),1.57-1.66 (2H, m), 1.75-1.85 (2H, m), 2.15-2.26 (6H, m), 2.29-2.41 (6H,m), 3.45-3.53 (4H, m), 3.63-3.71 (2H, m), 4.12 (2H, t), 4.20 (4H, s),6.37 (2H, s), 6.66-6.77 (3H, m), 9.81 (1H, s)

MS: APCI (+ve): 556 (M+H)

Example 56-Amino-2-butoxy-9-{3-[(3,4-dimethoxybenzyl)(3-morpholin-4-ylpropyl)amino]propyl}-7,9-dihydro-8H-purin-8-one

¹H NMR δ (DMSO-d₆) 0.90 (3H, t), 1.31-1.42 (2H, m), 1.43-1.54 (2H, m),1.55-1.65 (2H, m), 1.77-1.87 (2H, m), 2.12-2.26 (6H, m), 2.30-2.44 (4H,m), 3.30 (1H, s), 3.40-3.52 (6H, m), 3.65-3.76 (7H, m), 4.12 (2H, t),6.37 (2H, s), 6.73-6.77 (1H, m), 6.82 (1H, d), 6.89 (1H, d), 9.81 (1H,s)

MS: APCI (+ve): 558 (M+H)

Example 66-Amino-2-butoxy-9-{3-[(4-morpholin-4-ylbenzyl)(3-morpholin-4-ylpropyl)amino]propyl}-7,9-dihydro-8H-purin-8-one

¹H NMR δ (DMSO-d₆) 0.82-0.95 (3H, m), 1.30-1.40 (2H, m), 1.43-1.53 (2H,m), 1.57-1.67 (2H, m), 1.76-1.86 (2H, m), 2.15-2.24 (6H, m), 2.30-2.39(4H, m), 2.99-3.09 (4H, m), 3.39 (2H, s), 3.44-3.54 (4H, m), 3.61-3.77(6H, m), 4.12 (2H, t), 6.38 (2H, s), 6.82 (2H, d), 7.10 (2H, d)

MS: APCI (+ve): 583 (M+H)

Example 76-Amino-2-butoxy-9-{3-[(3-morpholin-4-ylpropyl)(4-pyrimidin-2-ylbenzyl)amino]propyl}-7,9-dihydro-8H-purin-8-one

¹H NMR δ (DMSO-d₆) 0.87 (3H, t), 1.28-1.39 (2H, m), 1.47-1.55 (2H, m),1.56-1.64 (2H, m), 1.82-1.90 (2H, m), 2.13-2.26 (6H, m), 2.31-2.43 (4H,m), 3.46 (4H, t), 3.58 (2H, s), 3.67-3.75 (2H, m), 4.11 (2H, t), 6.36(2H, s), 7.40-7.48 (3H, m), 8.32 (2H, d), 8.89 (2H, d), 9.81 (1H, s)

MS: APCI (+ve): 576 (M+H)

Example 8 6-Amino-2-butoxy-9-{3-[[4-(methylthio)benzyl](3-morpholin-4-ylpropyl)amino]propyl}-7,9-dihydro-8H-purin-8-one

¹H NMR δ (DMSO-d₆) 0.90 (3H, t), 1.29-1.41 (2H, m), 1.43-1.52 (2H, m),1.56-1.66 (2H, m), 1.78-1.87 (2H, m), 2.14-2.24 (6H, m), 2.31-2.41 (4H,m), 2.44 (3H, s), 3.41-3.51 (6H, m), 3.69 (2H, t), 4.12 (2H, t), 6.38(2H, s), 7.19 (4H, dd), 9.81 (1H, s)

MS: APCI (+ve): 544 (M+H)

Example 9 6-Amino-2-butoxy-9-(3-{(3-morpholin-4-ylpropyl)[(2-oxo-2H-chromen-6-yl)methyl]amino}propyl)-7,9-dihydro-8H-purin-8-one

¹H NMR δ (DMSO-d₆) 0.88 (3H, t), 1.28-1.39 (2H, m), 1.45-1.54 (2H, m),1.55-1.64 (2H, m), 1.79-1.88 (2H, m), 2.14-2.26 (6H, m), 2.34-2.46 (4H,m), 3.45 (4H, t), 3.55 (2H, s), 3.70 (2H, t), 4.10 (2H, t), 6.37 (2H,s), 6.47 (1H, d), 7.31 (1H, d), 7.54 (1H, dd), 7.61 (1H, d), 8.03 (1H,d), 9.80 (1H, s)

MS: APCI (+ve): 566 (M+H)

Example 106-Amino-2-butoxy-9-(3-{(3-morpholin-4-ylpropyl)[(2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)methyl]amino}propyl)-7,9-dihydro-8H-purin-8-one

¹H NMR δ (DMSO-d₆) 0.89 (3H, t), 1.26-1.41 (2H, m), 1.42-1.51 (2H, m),1.55-1.64 (2H, m), 1.76-1.89 (2H, m), 2.11-2.24 (6H, m), 2.27-2.44 (4H,m), 3.40-3.53 (6H, m), 3.62-3.76 (2H, m), 4.11 (2H, t), 6.37 (2H, s),7.02 (1H, d), 7.18 (1H, d), 7.45 (1H, s), 9.69-9.90 (1H, m)

MS: APCI (+ve): 571 (M+H)

Example 116-Amino-2-butoxy-9-{3-[(3-morpholin-4-ylpropyl)(4-propoxybenzyl)amino]propyl}-7,9-dihydro-8H-purin-8-one

¹H NMR δ (DMSO-d₆) 0.83-1.02 (6H, m), 1.29-1.43 (2H, m), 1.42-1.56 (2H,m), 1.54-1.87 (6H, m), 2.12-2.26 (6H, m), 2.28-2.42 (4H, m), 3.41 (2H,s), 3.43-3.53 (4H, m), 3.62-3.72 (2H, m), 3.88 (2H, t), 4.12 (2H, t),6.37 (2H, s), 6.81 (2H, d), 7.15 (2H, d), 9.81 (1H, s)

MS: APCI (+ve): 556 (M+H)

Example 126-Amino-2-butoxy-9-{3-[(3,5-dimethoxybenzyl)(3-morpholin-4-ylpropyl)amino]propyl}-7,9-dihydro-8H-purin-8-one

¹H NMR δ (DMSO-d₆) 0.90 (3H, t), 1.32-1.40 (2H, m), 1.45-1.53 (2H, m),1.56-1.65 (2H, m), 1.77-1.85 (2H, m), 2.17-2.25 (6H, m), 2.31-2.43 (4H,m), 3.44 (2H, s), 3.48 (4H, t), 3.64-3.70 (2H, m), 3.71 (6H, s), 4.11(2H, t), 6.33 (1H, t), 6.38 (2H, s), 6.47 (2H, d)

MS: APCI (+ve): 558 (M+H)

Example 136-Amino-2-butoxy-9-{3-[(2,4-dimethoxybenzyl)(3-morpholin-4-ylpropyl)amino]propyl}-7,9-dihydro-8H-purin-8-one

¹H NMR δ (DMSO-d₆) 0.90 (3H, t), 1.30-1.41 (2H, m), 1.42-1.53 (2H, m),1.56-1.67 (2H, m), 1.75-1.86 (2H, m), 2.14-2.25 (6H, m), 2.30-2.41 (4H,m), 3.40 (2H, s), 3.45-3.53 (4H, m), 3.66 (2H, t), 3.73 (6H, s), 4.12(2H, t), 6.37 (2H, s), 6.39-6.44 (1H, m), 6.48 (1H, d), 7.14 (1H, d),9.80 (1H, s)

MS: APCI (+ve): 558 (M+H)

Example 14(4-{[[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl](3-morpholin-4-ylpropyl)amino]methyl}phenoxy)acetonitrile

¹H NMR δ (DMSO-d₆) 0.90 (3H, t), 1.30-1.42 (2H, m), 1.43-1.53 (2H, m),1.56-1.66 (2H, m), 1.77-1.86 (2H, m), 2.12-2.25 (6H, m), 2.30-2.43 (4H,m), 3.42-3.51 (6H, m), 3.68 (2H, t), 4.12 (2H, t), 5.13 (2H, s), 6.38(2H, s), 6.96 (2H, d), 7.26 (2H, d), 9.81 (1H, s)

MS: APCI (+ve): 553 (M+H)

Example 156-Amino-2-butoxy-9-{3-[(3-morpholin-4-ylpropyl)(4-pyrrolidin-1-ylbenzyl)amino]propyl}-7,9-dihydro-8H-purin-8-one

¹H NMR δ (DMSO-d₆) 0.90 (3H, t), 1.32-1.41 (2H, m), 1.44-1.53 (2H, m),1.58-1.67 (2H, m), 1.78-1.84 (2H, m), 1.90-1.96 (4H, m), 2.15-2.26 (6H,m), 2.31-2.37 (4H, m), 3.15-3.21 (4H, m), 3.36 (2H, s), 3.49 (4H, t),3.67 (2H, t), 4.13 (2H, t), 6.37 (2H, s), 6.42 (2H, d), 7.02 (2H, d),9.80 (1H, s)

MS: APCI (+ve): 567 (M+H)

Example 166-Amino-2-butoxy-9-(3-{(3-morpholin-4-ylpropyl)[4-(1H-1,2,4-triazol-1-yl)benzyl]amino}propyl)-7,9-dihydro-8H-purin-8-one

¹H NMR δ (DMSO-d₆) 0.87 (3H, t), 1.28-1.39 (2H, m), 1.46-1.55 (2H, m),1.55-1.65 (2H, m), 1.80-1.90 (2H, m), 2.15-2.26 (6H, m), 2.29-2.46 (4H,m), 3.41-3.51 (4H, m), 3.56 (2H, s), 3.71 (2H, t), 4.10 (2H, t), 6.37(2H, s), 7.47 (2H, d), 7.76 (2H, d), 8.19 (2H, d), 9.84 (1H, s)

MS: APCI (+ve): 565 (M+H)

Example 17 6-Amino-2-butoxy-9-{3-[[4-(methylsulfonyl)benzyl](3-morpholin-4-ylpropyl)amino]propyl}-7,9-dihydro-8H-purin-8-one

The product from example 1 step (viii) (0.1 g), 4-methylsulphonylbenzylbromide (0.0673 g) and potassium carbonate (0.0373 g) were combined inDMF (1.5 mL) and stirred at RT for 15 hrs. The reaction mixture wasdiluted with methanol filtered and purified by RPHPLC to give titlecompound, 0.039 g

¹H NMR δ (DMSO-d₆) 0.82-0.98 (3H, m), 1.27-1.43 (2H, m), 1.43-1.55 (2H,m), 1.56-1.68 (2H, m), 1.79-1.91 (2H, m), 2.13-2.30 (6H, m), 2.33-2.42(4H, m), 3.18 (4H, s), 3.41-3.54 (2H, m), 3.61 (2H, s), 3.66-3.79 (2H,m), 4.12 (2H, t), 6.38 (2H, s), 7.57 (2H, d), 7.83 (2H, d), 8.14 (1H,s), 9.82 (1H, s)

MS: APCI (+ve): 576 (M+H)

Example 184-{[[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl](3-morpholin-4-ylpropyl)amino]methyl}-N-(tert-butyl)benzenesulfonamide

The title compound was prepared using the method of example 17

¹H NMR δ (DMSO-d₆) 0.89 (3H, t), 1.06 (9H, s), 1.32-1.43 (2H, m),1.40-1.51 (2H, m), 1.54-1.69 (2H, m), 1.76-1.91 (2H, m), 2.11-2.24 (6H,m), 2.25-2.40 (4H, m), 3.42-3.50 (4H, m), 3.57 (2H, s), 3.64-3.78 (2H,m), 4.12 (2H, t), 6.38 (2H, s), 7.39-7.53 (3H, m), 7.74 (2H, d), 8.15(1H, s)

MS: APCI (+ve): 633 (M+H)

Example 196-Amino-2-butoxy-9-{3-[[4-(hydroxymethyl)benzyl](3-morpholin-4-ylpropyl)amino]propyl}-7,9-dihydro-8H-purin-8-one

¹H NMR δ (DMSO-d₆) 0.90 (3H, t), 1.31-1.42 (2H, m), 1.44-1.54 (2H, m),1.56-1.67 (2H, m), 1.77-1.87 (2H, m), 2.15-2.25 (6H, m), 2.30-2.42 (4H,m), 3.45-3.50 (5H, m), 3.67 (2H, t), 4.13 (2H, t), 4.46 (2H, d), 5.09(1H, t), 6.37 (2H, s), 7.21 (4H, s), 9.81 (1H, s)

MS: APCI (+ve): 528 (M+H)

Example 206-Amino-9-(3-{benzyl[2-(dimethylamino)ethyl]amino}propyl)-2-butoxy-7,9-dihydro-8H-purin-8-one

(i) 9-(3-Chloropropyl)-2-butoxy-8-methoxy-9H-purin-6-amine

The product of example 1 step (v) (50 g) was added in portions over 10minutes to a rapidly stirred mixture of potassium carbonate (60 g) and1-bromo-3-chloropropane (21 ml) in dimethylformamide (400 ml) at ambienttemperature and the mixture stirred for 3 hours. The mixture was dilutedwith water and extracted with ethyl acetate. The combined extracts werewashed with water and dried. The crude product was recrystallised fromacetonitrile. Yield 29.83 g.

MS: ESI (+ve): 314

(ii) 6-Amino-9-(3-chloropropyl)-2-butoxy-7,9-dihydro-8H-purin-8-one

The product of step (i) (29.8 g) was dissolved in methanol (60 ml) andtreated with 4M hydrogen chloride in dioxane (60 ml). The mixture wasstirred at room temperature for 2 hours, cooled to 0° C. and neutralisedwith 3.5% aqueous ammonia solution. The solid was filtered off, washedwith water then methanol and dried Yield 27.2 g.

¹H NMR δ (DMSO-d₆) 9.88 (1H, s), 6.41 (2H, s), 4.15 (2H, t), 3.80 (2H,t), 3.65 (2H, t), 2.14-2.07 (2H, m), 1.68-1.61 (2H, m), 1.43-1.34 (2H,m), 0.92 (3H, t).

(iii)6-Amino-2-butoxy-9-(3-{[2-(dimethylamino)ethyl]amino}propyl)-7,9-dihydro-8H-purin-8-one,hydrochloride

The product of step (ii) (16 g), DMSO (16 ml) andN,N-dimethylethylenediamine (120 ml) was heated at 80° C. for 4 h thenevaporated under reduced pressure. The residue was azeotroped withacetonitrile then heated under reflux in acetonitrile (250 ml) for 30min then cooled to 0° C. for 1 h. The solid was filtered off and dried.Yield 15.32 g.

¹H NMR δ (DMSO-d₆) 10.60 (1H, brs), 6.68 (2H, s), 4.15 (2H, t), 3.74(2H, t), 2.96 (2H, t), 2.97 (2H, t), 2.54-2.51 (2H, m), 2.22 (6H, s),2.02-1.95 (2H, m), 1.68-1.61 (2H, m), 1.44-1.35 (2H, m), 0.92 (3H, t).

MS: ESI (+ve): 352

(iv)6-Amino-9-(3-{benzyl[2-(dimethylamino)ethyl]amino}propyl)-2-butoxy-7,9-dihydro-8H-purin-8-one

The product from step (iii) (0.1 g) and benzaldehyde (0.0362 g, 0.0347ml) were combined in NMP (4 mL) and stirred at RT for 15 mins. Sodiumtriacetoxyborohydride (0.0904 g) was added. The reaction mixture wasstirred for 16 h. The reaction mixture was diluted with methanol andpurified by RP-prep-HPLC 75:05 NH3:acetonitrile over 15 mins to givetitle compound (0.068 g)

¹H NMR δ (DMSO-d₆) 0.90 (3H, t), 1.31-1.42 (2H, m), 1.54-1.65 (2H, m),1.77-1.88 (2H, m), 2.04 (6H, s), 2.21-2.28 (2H, m), 2.39-2.47 (4H, m),3.53 (2H, s), 3.64-3.72 (2H, m), 4.12 (2H, t), 6.40 (2H, s), 7.15-7.25(1H, m), 7.28 (4H, s)

MS: APCI (+ve): 442 (M+H)

Example 216-Amino-9-{3-[benzyl(1-methylpiperidin-4-yl)amino]propyl}-2-butoxy-7,9-dihydro-8H-purin-8-one

The title compound was prepared by the method of example 1 using1-methylpiperidin-4-amine.

¹H NMR δ (DMSO-d₆) 0.83-0.98 (3H, m), 1.30-1.54 (4H, m), 1.54-1.67 (3H,m), 1.67-1.80 (3H, m), 2.09 (4H, s), 2.31-2.47 (4H, m), 2.70-2.80 (2H,m), 3.55 (2H, s), 3.59-3.69 (2H, m), 4.12 (2H, t), 6.36 (2H, s),7.12-7.33 (5H, m), 9.78 (1H, s)

MS: APCI (+ve): 468 (M+H)

1. A compound of formula (I):

wherein R¹ represents hydrogen, hydroxyl, C₁-C₆ alkoxy, C₂-C₅alkoxycarbonyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, or a C₆-C₁₀ aryl,C₅-C₁₀ heteroaryl or C₃-C₈ cycloalkyl group, each group being optionallysubstituted by one or more substituents independently selected fromhalogen, hydroxyl, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, C₂-C₅ alkoxycarbonyl, amino (NH₂) and di-C₁-C₆ alkylamino;Y¹ represents a single bond or C₁-C₆ alkylene; X¹ represents a singlebond or an oxygen or sulphur atom or sulphonyl (SO₂) or NR³; Z¹represents a C₂-C₆ alkylene or C₃-C_(s) cycloalkylene group, each ofwhich may be optionally substituted by at least one hydroxyl; X²represents NR⁴, CONR⁴, NR⁴CO, SO₂NR⁴, NR⁴CONR⁵, NR⁵CONR⁴, SO₂, CO orNR⁵CSNR⁵; Y² represents a single bond or C₁-C₆ alkylene; n is 0, 1 or 2;each R² group independently represents halogen, cyano, S(O)_(m)R⁹, OR¹⁰,SO₂NR¹⁰R¹¹, CONR¹⁰R¹¹, NR⁷R⁸, NR¹⁰SO₂R⁹, NR¹⁰CO₂R⁹, NR¹⁰COR⁹, C₆-C₁₀aryl, C₅-C₁₀ heteroaryl, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl orC₃-C₈ cycloalkyl group, the latter six groups being optionallysubstituted by one or more substituents independently selected fromhalogen, cyano, S(O)_(m)R¹², OR¹³, SO₂NR¹³R¹⁴, CONR¹³R¹⁴, NR⁷R⁸,NR¹³SO₂R¹², NR¹³CO₂R¹², NR¹³COR¹², C₁-C₆ alkyl or C₃-C₈ cycloalkyl; R³represents hydrogen or C₁-C₆ alkyl; R⁴ represents hydrogen or a 3- to8-membered saturated heterocyclic ring comprising a ring group O or NR⁶,or R⁴ represents a C₁-C₆ alkylene optionally substituted by one or moresubstituents independently selected from NR⁷R⁸ or R⁶; R⁵ representshydrogen or a C₁-C₆ alkyl or C₃-C₆ cycloalkyl group, each of which maybe optionally substituted by one or more substituents independentlyselected from halogen, hydroxyl and NR⁷R⁸; R⁶ represents hydrogen,CO₂R⁹, SO₂R⁹, COR⁹, SO₂NR¹⁰R¹¹, CONR¹⁰R¹¹, a 3- to 8-membered saturatedheterocyclic ring comprising a ring group NR⁹, or (i) a C₆-C₁₀ aryl orC₅-C₁₀ heteroaryl group, each of which may be optionally substituted byone or more substituents independently selected from halogen, cyano,oxo, carboxyl, S(O)_(m)R¹², OR¹³, SO₂NR¹³R¹⁴, CONR¹³R¹⁴, NR¹³R¹⁴, NR¹³SO₂R¹², NR¹³ CO₂R¹², NR¹³COR¹², C₁-C₆ alkyl and C₁-C₃ haloalkyl, or (ii)a C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl or C₃-C₈ cycloalkyl group,each of which may be optionally substituted by one or more substituentsindependently selected from halogen, cyano, C₃-C₈ cycloalkyl, OR¹⁵,S(O)_(p)R¹⁶, CO₂R¹⁶, NR¹⁷R¹⁸, CONR¹⁷, R¹⁸, NR¹⁷COR¹⁶, SO₂NR¹⁷R¹⁸,NR¹⁷SO₂R¹⁶ and substituents defined in (i) above; R⁷, R⁸, R¹³, R¹⁴, R¹⁵,R¹⁹, R²⁰, R²², R²³, R²⁴ and R²⁵ each independently represent hydrogen,C₁-C₆ alkyl or C₃-C₆ cycloalkyl; or R⁷ and R⁸ together with the nitrogenatom to which they are attached form a 3- to 8-membered saturatedheterocyclic ring comprising a ring nitrogen atom and optionally one ormore further heteroatoms independently selected from nitrogen, oxygen,sulphur and sulphonyl, the heterocyclic ring being optionallysubstituted by one or more substituents independently selected fromhalogen, hydroxyl, carboxyl, cyano, OR²¹, S(O)_(q)R²¹, NR²²R²³, C₁-C₆alkyl and C₃-C₈ cycloalkyl; R⁹, R¹⁶ and R²¹ each independently representa C₁-C₆ alkyl or C₃-C₆ cycloalkyl group, each of which may be optionallysubstituted by one or more substituents independently selected fromhalogen, carboxyl, hydroxyl and NR¹⁹R²⁰; either R¹⁰ represents hydrogenor a C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl or C₃-C₈ cycloalkylgroup, each of which may be optionally substituted by one or moresubstituents independently selected from halogen, hydroxyl, carboxyl,cyano, OR²¹, S(O)_(q)R²¹, NR²²R²³ and C₃-C₈ cycloalkyl, and R¹¹represents hydrogen or a C₁-C₆ alkyl or C₃-C₆ cycloalkyl group, each ofwhich may be optionally substituted by one or more substituentsindependently selected from halogen, hydroxyl and NR²⁴R²⁵; or R¹⁰ andR¹¹ together with the nitrogen atom to which they are attached form a 3-to 8-membered saturated heterocyclic ring comprising at least oneheteroatom or heterogroup selected from nitrogen, oxygen, sulphur andsulphonyl, the heterocyclic ring being optionally substituted by one ormore substituents independently selected from halogen, hydroxyl,carboxyl, cyano, OR²¹, S(O)_(q)R²¹, NR²²R²³, C₁-C₆ alkyl and C₃-C₈cycloalkyl; R¹² represents C₁-C₆ alkyl or C₃-C₆ cycloalkyl; R¹⁷ and R¹⁸are defined as for R¹⁰ and R¹¹ respectively; m, p and q eachindependently represent 0, 1 or 2; and A represents a monocyclic orbicyclic C₆-C₁₀ aryl or a monocyclic or bicyclic C₅-C₁₂ heteroaryl groupcontaining 1-3 heteroatoms; or a pharmaceutically acceptable saltthereof.
 2. The compound according to claim 1 wherein X¹ representsoxygen, or a pharmaceutically acceptable salt thereof.
 3. The compoundaccording to claim 1 wherein R¹ represents hydrogen, or apharmaceutically acceptable salt thereof.
 4. The compound according toclaim 1 wherein Y¹ represents C₁-C₆ alkylene, or a pharmaceuticallyacceptable salt thereof.
 5. The compound according to claim 1 wherein Z¹is C₂-C₆ alkylene, or a pharmaceutically acceptable salt thereof.
 6. Thecompound according to claim 1 wherein X² represents N—R⁴, or apharmaceutically acceptable salt thereof.
 7. The compound according toclaim 1 wherein Y² represents C₁-C₆ alkylene, or a pharmaceuticallyacceptable salt thereof.
 8. The compound according to claim 1 wherein Arepresents phenyl, or a pharmaceutically acceptable salt thereof.
 9. Thecompound according to claim 1 selected from:6-Amino-9-{3-[benzyl(3-morpholin-4-ylpropyl)amino]propyl}-2-butoxy-7,9-dihydro-8H-purin-8-one;6-Amino-2-butoxy-9-{3-[(4-isopropoxybenzyl)(3-morpholin-4-ylpropyl)amino]propyl}-7,9-dihydro-8H-purin-8-one;6-Amino-2-butoxy-9-{3-[(4-methoxybenzyl)(3-morpholin-4-ylpropyl)amino]propyl}-7,9-dihydro-8H-purin-8-one;6-Amino-2-butoxy-9-{3-[(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(3-morpholin-4-ylpropyl)amino]propyl}-7,9-dihydro-8H-purin-8-one;6-Amino-2-butoxy-9-{3-[(3,4-dimethoxybenzyl)(3-morpholin-4-ylpropyl)amino]propyl}-7,9-dihydro-8H-purin-8-one;6-Amino-2-butoxy-9-{3-[(4-morpholin-4-ylbenzyl)(3-morpholin-4-ylpropyl)amino]propyl}-7,9-dihydro-8H-purin-8-one;6-Amino-2-butoxy-9-{3-[(3-morpholin-4-ylpropyl)(4-pyrimidin-2-ylbenzyl)amino]propyl}-7,9-dihydro-8H-purin-8-one;6-Amino-2-butoxy-9-{3-[[4-(methylthio)benzyl](3-morpholin-4-ylpropyl)amino]propyl}-7,9-dihydro-8H-purin-8-one;6-Amino-2-butoxy-9-(3-{(3-morpholin-4-ylpropyl)[(2-oxo-2H-chromen-6-yl)methyl]amino}propyl)-7,9-dihydro-8H-purin-8-one;6-Amino-2-butoxy-9-(3-{(3-morpholin-4-ylpropyl)[(2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)methyl]amino}propyl)-7,9-dihydro-8H-purin-8-one;6-Amino-2-butoxy-9-{3-[(3-morpholin-4-ylpropyl)(4-propoxybenzyl)amino]propyl}-7,9-dihydro-8H-purin-8-one;6-Amino-2-butoxy-9-{3-[(3,5-dimethoxybenzyl)(3-morpholin-4-ylpropyl)amino]propyl}-7,9-dihydro-8H-purin-8-one;6-Amino-2-butoxy-9-{3-[(2,4-dimethoxybenzyl)(3-morpholin-4-ylpropyl)amino]propyl}-7,9-dihydro-8H-purin-8-one;(4-{[[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl](3-morpholin-4-ylpropyl)amino]methyl}phenoxy)acetonitrile;6-Amino-2-butoxy-9-{3-[(3-morpholin-4-ylpropyl)(4-pyrrolidin-1-ylbenzyl)amino]propyl}-7,9-dihydro-8H-purin-8-one;6-Amino-2-butoxy-9-(3-[(3-morpholin-4-ylpropyl)[4-(1H-1,2,4-triazol-1-yl)benzyl]amino1 propyl)-7,9-dihydro-8H-purin-8-one;6-Amino-2-butoxy-9-{3-[[4-(methylsulfonyl)benzyl](3-morpholin-4-ylpropyl)amino]propyl}-7,9-dihydro-8H-purin-8-one;4-{[[3-(6-Amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl](3-morpholin-4-ylpropyl)amino]methyl}-N-(tert-butyl)benzenesulfonamide;6-Amino-2-butoxy-9-{3-[[4-(hydroxymethyl)benzyl](3-morpholin-4-ylpropyl)amino]propyl}-7,9-dihydro-8H-purin-8-one;6-Amino-9-(3-{benzyl[2-(dimethylamino)ethyl]amino}propyl)-2-butoxy-7,9-dihydro-8H-purin-8-one;and6-Amino-9-{3-[benzyl(1-methylpiperidin-4-yl)amino]propyl}-2-butoxy-7,9-dihydro-8H-purin-8-one,and pharmaceutically acceptable salts thereof.
 10. A pharmaceuticalcomposition comprising a compound of formula (I) or a pharmaceuticallyacceptable salt thereof as claimed in claim 1 in association with apharmaceutically acceptable adjuvant, diluent or carrier.
 11. A processfor the preparation of a pharmaceutical composition as claimed in claim9 comprising mixing the compound or a pharmaceutically acceptable saltthereof with the pharmaceutically acceptable adjuvant, diluent orcarrier.
 12. A pharmaceutical product comprising, in combination, two ormore active ingredients including a first active ingredient which is acompound of formula (I) as defined in claim 1, and a second activeingredient which is selected from: a phosphodiesterase inhibitor, a β2adrenoceptor agonist, a modulator of chemokine receptor function, aninhibitor of kinase function, a protease inhibitor, a glucocorticoid, ananticholinergic agent and a non-steroidal glucocorticoid receptoragonist.